Abstract

Background: Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa.

Results: We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the under weight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing.

Limitations: Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels.

Conclusion: Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

Acknowledgements: We thank Nina Nagelmann for her skillful technical support during the fMRI sessions. The study was supported by grants of Innovative Medizinische Forschung (IMF) of the Medical Faculty of Münster (DA120309 to UD and DA211012 to U. Dannlowski), and Rolf-Dietrichs-Stiftung (ZUW80037 to U. Dannlowski).

Contributors: A. Stuhrmann participated in the experimental design, performed the patient recruitment and data collection, performed the data analysis and wrote the manuscript. K. Dohm, R. Redlich, D. Grotegerd and A.V. Rauch participated in the data collection and data management, supported the data analysis, and participated in writing the article. H. Kugel and W. Heindel were responsible for planning and performing the fMRI data collection, designed the MRI sequence, supervised the fMRI data analysis and interpretation of the data. P. Zwanzger, P. Zwitserlood, T. Susulw and V. Arolt participated in designing the experiment, supervised the patient recruitment and data collection, and provided theoretical input for the interpretation of the data. T. Suslow furthermore designed the fMRI paradigm. U. Dannlowski designed the experiment, supervised the data collection and data analysis and the writing of the manuscript. All authors read, corrected and approved the final version of the manuscript.